Project Summary There are currently no effective targeted therapies for oral squamous cell carcinoma (OSCC), which includes cancers of the oral cavity and oropharynx, a disease that results in ~300,000 deaths each year worldwide. There is an urgent need to develop new therapeutic options to prevent and treat OSCC. A striking finding from the recent deep sequencing of the OSCC genomic landscape was the remarkable multiplicity and diversity of genetic alterations in this malignancy. The emerging picture, however, is that most fall within only a few major driver biological processes, including mitogenic signaling with particular emphasis on aberrant activation of the PI3K/mTOR pathway. Among them, PIK3CA, encoding the PI3K? catalytic subunit, is the most commonly mutated oncogene in OSCC (~20%), with a significant enrichment in (HPV)-associated tumors (25%). Our team has focused on the study of oncogenic signaling circuitries driving OSCC initiation and progression, aimed at identifying novel druggable targets for OSCC prevention and treatment. These efforts led to our early discovery that the persistent activation of the PI3K/mTOR signaling circuitry is the most frequent dysregulated signaling mechanism in OSCC, and that PI3K/mTOR inhibition exerts potent antitumor activity in a large series of genetically-defined and chemically-induced OSCC models. These findings provided the rationale for launching a multi-institutional Phase II clinical trial (NCT01195922), targeting mTOR in OSCC, which was recently completed and achieved encouraging results. However, 80% of the OSCC lesions lack driver PIK3CA mutations, and to date, we cannot predict the sensitivity or resistance to EGFRi and PI3K/mTORi in the context of an individual tumor, which may help explain prior treatment failures with PI3K/mTORi in unselected advanced OSCC patients. We have also shown that PIK3CA mutations may underlie cetuximab resistance, which can be overcome by mTOR inhibition. We will investigate the therapeutic potential of co-targeting the EGFR- PI3K/mTOR signaling circuitry based on the genetic stratification of PI3K/mTOR network subtypes, alone or combined with immune oncology agents with the goal to develop novel precision therapeutic approaches for OSCC. To this end, we will exploit the emerging information about the OSCC genomic landscape to a) identify alterations driving PI3K/mTOR activation in the OSCC lesions that lack PIK3CA mutation and explore their contribution to cetuximab resistance and sensitivity, b) identify novel systems vulnerabilities associated with cetuximab and PI3K/mTORi sensitization and c) establish the impact of targeting and co-targeting the EGFR- PI3K/mTOR signaling network on the tumor and immune microenvironment, and response to novel immune oncology agents. Ultimately, our efforts will a) overcome EGFR-PI3K/mTORi resistance mechanisms via network-based co-targeting strategies, b) increase the efficacy of novel immune checkpoint inhibitors by targeting oncogenic circuities, and c) inform the molecular stratification of OSCC for patient selection in future precision and immune oncology trials.